Oxamic acid derivatives

ABSTRACT

Anti-allergic agents of aromatic oxamic acid derivation present the following formula: ##STR1## in which A is a member selected from the group consisting of α-naphthyl, β-naphthyl, phenyl, 2,6-di-chlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkoxy, hydroxy (lower)alkoxy, 2-(oxalyloxy) ethoxy, benzyloxy, N-mono- and di-lower alkylamino(lower)alkoxy, halo, sulfamyl, polyhalo(lower)alkyl, carbamyl, N-lower alkylcarbamyl, nitro, mono and di lower alkylamino, carboxy, lower alkylcarbonyl, carb(lower)alkoxy, phenoxy(lower)alkoxy, and oxalamidophenoxy radicals; 
     And pharmaceutically acceptable salts thereof.

RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 669,565, filed Mar. 23, 1976, now U.S. Pat. No. 4,069,343, which application is a continuation-in-part of Ser. No. 542,465, filed Jan. 20, 1975, now U.S. Pat. No. 3,966,965, which application in turn is a continuation-in-part of Ser. No. 344,466, filed Mar. 23, 1973, now abandoned.

BACKGROUND OF THE INVENTION

Atopic immediate sensitivity is the chief manifestation found in animals suffering from bronchial asthma, seasonal pollinosis (e.g. hay fever), allergic rhinitis, urticaria, allergic conjunctivitis, food allergies and anaphylactoid reactions. The substances most frequently responsible for clinically manifest sensitivities are plant pollen, animal feathers and danders, dust, milk and wheat, whether inhaled or ingested.

Atopic hypersensitivity is found in man, dog and other animals. Its occurrance is exceptionally found in the lower animals.

The presence of antibodies associated with atopic hypersensitivity reactions in the host serum is established by the passive sensitization of the skin of a normal recipient, after injection of serum from a sensitized host into a skin site followed by injection of antigen into the same area 24 hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction.

The antibody associated with atopic hypersensitivity possesses distinctive features in that it does not in all forms precipitate with its antigen, fails to pass the placenta from mother to fetus, has special affinity for the skin, frequently lacks specificity foward an individual antigenic factor and is usually labile at about 56° C. after two hours.

The homocytotropic antibody found in or induced in the rat is related in function and reaction to immunoglobulin E (reagin or IgE) found in the human. The correlation between homocytotropic antibody in the rat and IgE in the human has been established through the common effects obtained from chemical reactions, immunological reactions and drug responses in the two species hosting those antibodies. In the human, reagin is the antibody responsible for atopic immediate hypersensitive reactions. In the rat, the homocytotropic antibody is responsible for atopic immediate hypersensitive reactions.

In theory, reagin, influences the cell membrane of a mast cell by reacting with an antigen, to initiate the reaction(s) within the mast cell which ultimately releases a mediator such as Bradykinin, SRS-A (slow reacting substance-A), histamine and other unknown substances. The mediator effects a change in surrounding cell wall permeability permitting a rapid change in flow or exudance of mediator(s) from the cells, resulting in an allergic attack symptom. The various methods commonly employed to relieve the symptoms of allergic attack, none of which are considered to be quite acceptable, are to (1) avoid attack by the antigen, (2) block the production of antibody with an immuno-suppressant, (3) block the action of the mediators on the cell under attack by administration of anti-histaminics, anti-5-hydroxy-tryptamines(5-HT) or anti-inflammatories, or (4) stimulate the cell under attack to negate the action of the mediator through the action of bronchodilators such as Isuprel® or a Xanthine.

The only compound known to date to operate as an anti-allergic by blocking reaction(s) within the mast cells, thereby preventing the production and release of mediators, is disodium cromoglycate (INTAL®).

Derivatives of oxamic acids have been employed in the past as intermediates for polymer formation and as tools for chemical research. Each of the known oxamic acid derivatives included as part of the new use aspect of this application is accompanied with a reference citation in the working examples, infra.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a process for preventing the release of pharmacological mediators from an immediate hypersensitivity reaction between reaginic type antibodies and an antigen, thereby preventing the symptoms manifest in bronchial asthma, seasonal pollinosis, allergic rhinitis, urticaria, allergic conjunctivities, food allergy and anaphylactoid reactions of a sensitized animal, which comprises prophylactically administering to said animal an effective amount of a compound of the formula: ##STR2## in which A is a member selected from the group consisting of α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl, and substituted phenyl moieties containing from one to three substituents in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkoxy, hydroxy(lower)alkoxy, 2-(oxalyloxy) ethoxy, benzyloxy, N-mono- and di- lower alkylaminoalkoxy, halo, sulfamyl, polyhalo(lower)-alkyl, carbamyl, N-lower alkylcarbamyl, nitro, mono- and di-lower alkylamino, carboxy, lower alkylcarbonyl, carb(lower)alkoxy, phenoxy(lower)alkoxy and oxalamidophenoxy radicals;

and pharmaceutically acceptable salts thereof.

The preferred method aspect of this invention comprises administering to a sensitized animal a compound which, in minimal dosage quantity, will suppress the allergic response to a degree of or in excess of 75 percent of the characteristic wheal size of sensitized skin tissue, which compounds present the structural formula: ##STR3## in which

A is α-naphthyl, β-naphthyl, phenyl, 2,6-dichlorophenyl or a substituted phenyl moiety containing from one to three substituents, in any of the 2,3,4 and 5 positions of the phenyl ring, independently selected from the group consisting of lower alkyl, fluoro, lower alkoxy, hydroxy(lower)alkoxy, N-mono- or di(lower)alkylamino(lower)alkoxy, (lower)alkylthio, carbamyl, carb(lower)alkoxy, 2-(oxalyloxy) ethoxy, trifluoromethyl, nitro, and phenoxy(lower)alkoxy;

and pharmaceutically acceptable salts thereof.

The novel aromatic oxamic acid derivatives form an additional aspect of this invention.

The aromatic oxamic acid derivatives present the formula: ##STR4## in which A is a member selected from the group consisting of 3-fluorophenyl, 4-carbamylphenyl, 2-nitro-4-trifluoromethylphenyl, 4-nitro-3-trifluoromethylphenyl, 5-chloro-2-sulfamylphenyl and ##STR5## wherein R¹ is a member selected from the group consisting of hydroxyl, lower alkyl, lower alkoxy, lower alkylamino and amino radicals;

R² is a member selected from the group consisting of hydrogen, lower alkoxy, di(lower)alkylamino(lower)alkoxy, hydroxy(lower)alkoxy, phenoxy(lower)alkoxy, 2-(oxalyloxy)ethoxy and lower alkylthio radicals; with the proviso that when R¹ is hydroxy or lower alkoxy, R² is other than hydrogen;

R³ is a member selected from the group consisting of hydrogen, lower alkyl, and lower alkoxy radicals;

R⁴ is a member selected from the group consisting of --H, lower alkyl and lower alkoxy with the proviso that one of R², R³ and R⁴ must be other than hydrogen.

The term "lower" used throughout this application to modify alkyl, alkoxy, and the like, is intended to embrace univalent aliphatic hydrocarbon radicals containing from 1 to 6 carbon atoms. The term "halo" is used to embrace chlorine, bromine, iodine and fluorine.

Each of the carboxylic acids constituting this invention has been demonstrated in the form of their simple esters to relieve atopic allergic manifestations, when administered intraperitoneally to sensitized rats. Several of the compounds tested were found to be effective anti-allergy agents when administered orally to the sensitized animals.

The technique employed to establish the anti-allergic activity of the disclosed compounds is reported in Immunology, vol. 16, pp. 749-760 (1969) and involves four male Charles River rats (200-250 grams body weight) per group to provide a control, a host for administration of a standard anti-allergic compound (disodium cromoglycate) and animals for the test compound. The rats were injected intracutaneously on their shaved backs with sera from rats immunized with egg albumin and pertussis vaccine. Twenty-four hours after the initial injections, the test compound is administered intraperitoneally or orally at a dosage level of 200 milligrams per kilogram host body weight. Five minutes later one milliliter of a 0.5 percent solution of Evans blue dye and 8 milligrams of egg albumin is injected intravenously. After forty minutes, the animal is sacrificed and the bleb size on its back is measured. The mean bleb size for the animals administered the test compound is calculated and the percent inhibition is determined by comparison with the control animal. A representative number of the compounds were tested at dosage levels considerably below 200 milligrams per kilogram host body weight to establish the activity of the compounds at minimal concentrations as low as 3 milligrams per kilogram host body weight.

Although the mechanism by which the compounds of this invention function is not absolutely known, applicants have found that the compounds of this invention, in a manner believed to be similar to the function of INTAL^(R), block reaction(s) in the mast cell leading to the production and release of mediators.

The compounds of this invention permit the occurrence of a non-productive antigen-antibody interaction. They effectively block the IgE type reaction and have little or no effect on the other immunoglobulins such as IgG, IgM, IgA and IgD.

The compounds of this invention have no pharmacological response pattern similar to known anti-allergics in that they have no anti-hypertensive activity (no cardiovascular effect, etc.), they have no analogesic activity, they have no central nervous system activity, they have no immunosuppressive activity, they have no activity against histamine, serotonin, Bradykinin, etc. and they have no endocrinological activity.

In sum, the compounds of this invention block the release of mediators commonly resulting from the antigen-antibody reaction as exemplified in a passive cutaneous anaphylaxis test (PCA) using rat homocytotropic antibody--a known correlate of human reaginic antibody.

By analogy to disodium cromoglycate and its activity correlation between standard test animals, domestic animals and man, the compounds of this invention have been established as anti-allergic agents suitable for the same uses at analogous doses and through the same routes of administration as INTAL®. Several of the compounds of this invention have been found to be effective anti-allergic agents when administered orally. The orally active compounds of special interest are the methyl, ethyl and i-propyl oxanilate, ethyl 3'-methyloxanilate, ethyl 4'-methoxyoxanilate, ethyl and secondary butyl 2'-carbamyl -3'-methoxyoxanilate, ethyl 4'-nitro-3'-(trifluoromethyl)oxanilate and ethyl 1-naphthyloxamate, 2'-carbamyl-3'-(2-hydroxypropoxy)oxanilic acid ethyl ester, (2-carbamyl-3, 5-dimethoxyphenyl)oxamic acid ethyl ester, oxalic acid (2-[2-aminocarbonyl-3-ethoxy carbonylcarbonylaminophenoxy]ethyl)ethyl ester, [2-carbamyl-3(2-hydroxyethoxy)phenyl]oxamic acid ethyl ester, 3-benzyloxy-2-carbamylphenyl)oxamic acid ethyl ester, (4-dimethylaminophenyl)oxamic acid ethyl ester, [2-(aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethyl ester, [2-carbamyl-3-(methylthio)phenyl]oxamic acid ethyl ester and [(2-aminocarbonyl- 3-methylsulfinylphenyl)amino]oxo acetic acid ethyl ester.

Thus, there is provided herewith a method for suppressing allergic manifestations of atopic immediate sensitivity in warm-blooded human and non-human animals, the latter including domesticated animals such as the mouse, rat, hamster, gerbil, dog, cat, sheep, goat, horse, cow, and the like, by administering an effective amount of one or more of the compounds disclosed in this application by oral, topical, parenteral, rectal, vaginal or inhalation routes. Since the compounds of this invention afford no pharmacological response pattern similar to or antagonistic to common anti-allergics, they may be administered in conjunction with known compounds effecting anti-histaminic, anti-hypertensive, analgesic, central nervous system depressant, immunosuppressive, anti-serotonin, anti-Bradykinin or endocrinological responses. In addition, those conventional adjuvants known to the art may be combined with the anti-allergics of this invention to provide compositions and solutions for administrative purposes, although it is considered desirable and feasible to employ the anti-allergics as neat or pure compounds without additives other than for purposes of providing suitable pharmaceutical solution or liquid or vapor suspensions.

The effective dose range in test animals has been established to be from about 1.5 milligrams per kilogram to a dosage resulting in 100 percent prevention of allergic responses at 5 milligrams per kilogram host body weight upon administration intraperitoneally. The oral dose range lies from about 1.5 milligrams per kilogram to 90 percent prevention of allergic response at 200 milligrams per kilogram host body weight. As an inhalant the dose is from that of INTAL®, (about 20 milligrams) to 1/20th that quantity administered as needed prior to attack. Thus the dosage contemplated for human use based upon the potency of the compounds administered lies from about 100 milligrams to 1 gram, preferably 250 milligrams to about 750 milligrams in unit dosage form to be administered when necessary and to the degree of the desired response, in single or plural doses under the guidance of a physician.

The compounds of this invention have not been found to be toxic to mice, the standard experimental animal in toxicity studies of this nature, at any administered dose up to and in excess of two grams per kilogram host body weight. No toxic level has been found in other standard test animals. The anti-allergic compounds of this invention appear to be free from side effects common to other anti-allergics such as sedation, dizziness, depression, etc.

The aromatic oxamic acid derivatives are generally prepared by reaction of an appropriately substituted aromatic amino or heterocyclic amino with an appropriately substituted oxalylchloride in the presence of an acid acceptor, such as pyridine, at ambient temperature. The technique employed in the preparation of each of the specifically disclosed compounds is presented in the following working examples either in detail or by citation of the appropriate literature, the latter being incorporated herein by reference. Throughout the following Examples, reference is made to CA (Chemical Abstracts), Zh. Obshch. Khim (The Journal of General Chemistry--Russia), Rec. Trav. Chim (Recueil des Travaux Chimique des Pays-Bas-Netherlands), Heilbron (Dictionary of Organic Compounds), Ber. Deut. Chem. (Berichte der deutschen chemischen Gesellschaft), J. Org. Chem. (Journal of Organic Chemistry), J.A.C.S. (Journal of the American Chemical Society) and Farmaco, Ed. Sci. (II Farmaco Scientifica Edition--Italy).

In the working examples, the number following the entitled compound refers to intraperitoneal/oral activity data obtained at a dosage level of 200 milligrams per kilogram host body weight, unless otherwise indicated. The activity data represents the percent inhibition of the mean bleb size of sensitized rats administered the named compound in accordance with the test procedure presented, supra. The oral data is representatively presented for those compounds exhibiting inhibition of fifty percent or more of the weal size in the test animals at 200 milligrams per kilogram host body weight unless otherwise indicated.

In the following examples, the various esters produced are readily converted to the corresponding free carboxylic acid by conventional techniques well known to the art; Example 26 illustrating one such process. The free carboxylic acids, active in their own right as anti-allergic agents, also represent intermediates for the production of esters, where the alcoholic moiety is to be tailored for lipide solubility, for the production of pharmaceutically acceptable salts such as the alkali metal and ammonium salts or an amine salt which is readily derived from such known pharmaceutically acceptable amines as diethylamine, di-(hydroxy ethyl)amine, N,N'-dibenzylethylenediamine, and the like, or for the production of an amide. Likewise, the expression "pharmaceutically acceptable salt" is intended to embrace those non-toxic acid addition salts which may be formed with either organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methane sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid and the like.

EXAMPLE 1 Oxanilic acid ethyl ester. 100/64.

The title compound is known in the literature: G. Tiere, Rec. Trav. Chim., 52, 420-4 (1933). It is crystallized from ethanol, m.p. 64°-67° C.

EXAMPLE 2 Oxanilic acid methyl ester. 100/52.

The title compound is known in the literature: Heilbron Dict. of Org. Cpds., IV, p. 32. (1965). It is crystallized from diethyl ether, m.p. 113°-116° C.

EXAMPLE 3 Oxanilic acid n-propyl ester. 82.

The title compound is known in the literature: Heilbron Dict. of Org. Cpds., Vol. IV, p. 32, (1965). It is crystallized from diethyl ether, m.p. 90°-92° C.

EXAMPLE 4 Oxanilic acid i-propyl ester. 100/60.

The title compound is known in the literature: Heilbron Dict. of Org. Cpds., Vol. IV, p. 32 (1965). It is crystallized from pentane, m.p. 51°-53° C.

EXAMPLE 5 Oxanilic acid phenyl ester. 59.

The title compound is known in the literature; R. Stolle et al., Ber. Deut. Chem., 54B, 1213-20 (1921). It is crystallized from ethanol, m.p. 136°-139° C.

EXAMPLE 6 2'-Carboxyoxanilic acid 1-ethyl ester. 50.

The title compound is known in the literature: J.A.C.S. 32, 119 (1910). It is crystallized from toluene, m.p. 182°-183° C.

EXAMPLE 7 2'-Carbamyloxanilic acid ethyl ester. 90.

The title compound is known in the literature: B. R. Baker et al., J. Org. Chem., 27, 4672 (1962). It is crystallized from ethanol, m.p. 160°-161° C.

EXAMPLE 8 2'-Methyloxanilic acid ethyl ester. 75.

The title compound is known in the literature: P. E. Todesco et. al., C.A. 61:419f. It is a liquid, b.p. 126° C./0.05 mm. Hg.

EXAMPLE 9 2'-Methoxyoxanilic acid ethyl ester. 100.

The title compound is known in the literature: C.A.:61 (4192). It is crystallized from benzene, m.p. 81°-85° C.

EXAMPLE 10 3'-Methoxyoxanilic acid ethyl ester. 38.

The title compound is known in the literature: P. A. Petyunin et. al., ZH. Obshch. Khim., 21, 1859-61 (1951). It is crystallized from methanol-water, m.p. 95°-98° C.

EXAMPLE 11 3'Trifluoromethyloxanilic acid ethyl ester. 64.

The title compound is known in the literature: A. Buruffini, et al., Farmaco, Ed. Sci., 22 (9), 717-34 (1967). It is crystallized from ethanol, m.p. 120°-123° C.

EXAMPLE 12 3'-Fluorooxanilic acid ethyl ester. 78.

m-Fluoroaniline (5.55 g., 0.05 mole) is condensed with 6.16 ml. (0.055 mole) of ethyl oxalyl chloride in 100 ml. dichloromethane in the presence of pyridine at about 10° C. with stirring, giving 9.26 g. of the title compound, m.p. 85°-89° C. after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₀ FNO₃ : Calc'd: C, 57.0; H, 4.78; N, 6.64. Found: C, 56.45; H, 4.87; N, 6.61.

EXAMPLE 13 3'-Methyloxanilic acid ethyl ester. 85.

The title compound is known in the literature: P. A. Petyunin et. al., Zh. Obshch. Khim., 24, 1078-82 (1954). It is crystallized from benzene-hexane, m.p. 56°-60° C.

EXAMPLE 14 4'-Carbamyloxanilic acid ethyl ester. 55.

p-Aminobenzamide (4.08 g., 0.03 mole) is condensed with 3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 2.85 g. of the title compound, m.p. 259°-264° C. (dec.), after crystallization from N,N-dimethylformamide.

Elemental Analysis for C₁₁ H₁₂ N₂ O₄ : Calc'd: C, 55.93; H, 5.12; N, 11.86. Found: C, 56.01; H, 5.24; N, 11.92.

EXAMPLE 15 4'-Methoxyoxanilic acid ethyl ester. 75/76.

The title compound is known in the literature: A. Piutti et. al., Br. Deut. Chem., 31, 330-336 (1898). It is crystallized from ethanol, m.p. 100°-104° C.

EXAMPLE 16 4'-Nitrooxanilic acid ethyl ester. 75.

The title compound is known in the literature: G. Tierie, Rec. Trav. Chim., 52, 420-4 (1933). It is crystallized from acetic acid, m.p. 169°-172° C.

EXAMPLE 17 4'-Methyloxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A. 61 (4192). It is crystallized from benzene-hexane, m.p. 65°-67° C.

EXAMPLE 18 2'-Carbamyl-3'-methoxyoxanilic acid ethyl ester. 100/94.

6-Amino-o-anisamide (8.75 g., 0.0527 mole) is condensed with 6.2 ml. (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 8.35 g. of the title compound, m.p. 170°-173° C., after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66.

EXAMPLE 19 2-Carboxy-3'-methoxyoxanilic acid ethyl ester. 54.

6-Amino-o-anisic acid (1.671 g., 0.01 mole) is condensed with 1.23 ml. (0.011 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 1 g. of the title compound, m.p. 142°-144° C., after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53,93; H, 4.90; N, 5.24. Found: C, 54.21; H, 4.99; N, 5.32.

EXAMPLE 20 2'-Carbamyl-3'-chlorooxanilic acid ethyl ester. 25.

2-Amino-6-chlorobenzamide (4.26 g., 0.025 mole) is condensed with 3.1 ml. (0.0275 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 5.28 g. of the title compound, m.p. 190°-193° C., after crystallization from ethanol.

Elemental Analysis for C₁₁ H₁₁ ClN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N, 10.35. Found: C, 49.08; H, 4.05; N, 10.72.

EXAMPLE 21 2'-Carboxy-3'-methoxyoxanilic acid 1-ethyl 2'-methyl ester. 78.

Methyl 6-methoxyanthranilic acid (3.62 g., 0.02 mole) is condensed with 2.46 ml. (0.022 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 3.51 g. of the title compound, m.p. 96°-99° C. after crystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98. Found: C, 55.56; H, 5.43; N, 5.18.

EXAMPLE 22 2'-Carbamyl-3'-(2-phenoxyethoxy)oxanilic acid ethyl ester. 75.

2-Phenoxyethanol (4.15 ml., 0.033 mole) is added to dimethylsulfoxyl sodium prepared from 1.39 g. of 57 percent sodium hydride and 40 ml. dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g. (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml. of dimethylsulfoxide at 30°-40° C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70° C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethyl acetate. The ethyl acetate solution is washed twice with H₂ O, brine, and dried with calcium sulfate. Evaporation of the ethyl acetate gives 8.5 g. of 2-nitro-6(2-phenoxyethoxy)benzonitrile, which is crystallized from 200 ml. ethyl alcohol, giving 6 g., m.p. 129°-137.5° C.

The crystallized 2-nitro-6-(2-phenoxyethoxy)benzonitrile (5.82 g., 0.0205 mole) is stirred in 116 ml. absolute ethanol at 50° C. and 3.62 ml. (0.0615 mole) 85 percent hydrazine hydrate is added, followed by small scoops of Raney nickel. The temperature is kept at 50°-60° C. while the Raney nickel is added, and after gas evolution and the exotherm ceases, the mixture is filtered through diatomaceous earth. The filter cake is washed with hot ethanol and the filtrate is concentrated, giving 2.804 g. of 2-amino-6-(2-phenoxyethoxy)benzamide m.p. 127°-130° C.

Elemental Analysis for C₁₅ H₁₆ N₂ O₃ : Calc'd: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.71; H, 6.36; N, 10.13.

2-Amino-6-(2-phenoxyethoxy)benzamide (2.8 g., 0.0103 mole) is condensed with 1.26 ml. (0.0113 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 1.62 g. of the title compound, m.p. 142°-145° C., after crystallization from ethanol.

Elemental Analysis for C₁₉ H₂₀ N₂ O₆ : Calc'd: C, 61.28; H, 5.41; N, 7.52. Found: C, 61.14; H, 5.57; N, 7.50.

EXAMPLE 23 2'-Carbamyl-3'-methoxyoxanilic acid methyl ester. 96.

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 12, giving 4.24 g. of the title compound, m.p. 195°-198° C., after crystallization from methanol.

Elemental Analysis for C₁₁ H₁₂ N₂ O₅ : Calc'd: C, 52.28; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40.

EXAMPLE 24 2'-Carbamyl-3'-methoxyoxanilic acid n-propyl ester. 96

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 4.25 ml. (0.033 mole) of n-propyl oxalyl chloride in a manner similar to example 12, giving 4.81 g. of the title compound, m.p. 158°-161° C., after crystallization from acetonitrile.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N, 10.00. Found: C, 55.92; H, 5.93; N, 10.34.

EXAMPLE 25 2'-Carbamyl-3'-methoxyoxanilic acid isopropyl ester. 57

6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 4.25 ml. (0.033 mole) of isopropyl oxalyl chloride in a manner similar to example 12, giving 4.74 g. of the title compound, m.p. 128°-132° C., after crystallization from benzene.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calc'd: C, 55.71; H, 5.75; N, 10.00. Found: C, 55.66; H, 5.93; N, 10.38.

EXAMPLE 26 2'-Carbamyl-3'-methoxyoxanilic acid. 48

2'-Carbamyl-3'-methoxyoxanilic acid ethyl ester (1.33 g., 0.005 mole) is stirred in 50 ml. water, and 5.0 ml. of N NaOH is slowly added, giving a solution. After 1/2 hour the solution is filtered, and the filtrate is acidified to pH 2 with N HCl, giving 0.71 g. of the title compound, m.p. 214°-215° C., after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₀ O₅ N₂ : Calc'd: C, 50.42; H, 4.23; N, 11.76. Found: C, 50.60; H, 4.35; N, 11.80.

EXAMPLE 27 N-(2-Carbamyl-3-methoxyphenyl)oxamide. 26

2'-Carbamyl-3'-methoxyoxanilic acid ethyl ester (5.0 g., 0.0188 mole) is added to 50 ml. of ethanol saturated with ammonia at 0°-5° C., and the mixture is stirred in an ice-bath for 2 hours, then filtered. The cake is washed with ethanol, giving 1.41 g. of the title compound, m.p. 252°-255° C., after crystallization from water.

Elemental Analysis for C₁₀ H₁₁ N₃ O₂ : Calc'd: C, 50.63; H, 4.67; N, 17.72. Found: C, 50.45; H, 4.70; N, 17.65.

EXAMPLE 28 2'-Carboxy-4'-methoxyoxanilic acid ethyl ester. 61

5-Methoxyanthranilic acid (1.67 g., 0.01 mole) is condensed with 1.23 ml. (0.011 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 1.32 g., of the title compound, m.p. 238°-243° C., after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₃ NO₆ : Calc'd: C, 53.93; H, 4.90; N, 5.24. Found: C, 53.99; H, 4.93; N, 4.99.

EXAMPLE 29 2'-Carbamyl-4'-chlorooxanilic acid ethyl ester. 58

2-Amino-5-chlorobenzamide (3.41 g., 0.02 mole) is condensed with 2.46 ml. (0.022 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 4.57 g. of the title compound, m.p. 204°-210° C., after crystallization from acetonitrile.

Elemental Analysis for C₁₁ H₁₁ ClN₂ O₄ : Calc'd: C, 48.8; H, 4.10; N, 10.35; Cl, 13.10. Found: C, 48.65; H, 3.98; N, 10.26; Cl, 12.84.

EXAMPLE 30 2'-Carbamyl-4'-nitrooxanilic acid ethyl ester. 59

2-Amino-5-nitrobenzamide (5.43 g., 0.03 mole) is condensed with 3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 6.54 g. of the title compound, m.p. 206°-209° C., after crystallization from ethanol.

Elemental Analysis for C₁₁ H₁₁ N₃ O₆ : Calc'd: C, 46.98; H, 3.94; N, 14.94. Found: C, 46,68; H, 3.96; N, 15.12.

EXAMPLE 31 4'-Methoxy-2'-nitrooxanilic acid ethyl ester. 84

The title compound is known in the literature: Zh. Obshch. Khim. 1, 2471-7 (1937). It is crystallized from ethanol, m.p. 154°-160° C.

EXAMPLE 32 2'-Nitro-4'-(trifluoromethyl)oxanilic acid ethyl ester. 29

4-Amino-4-nitrobenzotrifluoride (3.21 g., 0.03 mole) is condensed with 3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 3.84 g. of the title compound, m.p. 186°-188° C., after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 43.1; H, 2.96; N, 9.16. Found: C, 42.97; H, 3.02; N, 9.28.

EXAMPLE 33 2'-Carbamyl-5'-methoxyoxanilic acid ethyl ester. 91

2'-Nitro-4-methoxybenzonitrile (12.8 g) is reduced in a manner similar to example 22, giving 9.0 g. of 2-amino-p-anisamide, m.p. 152°-156° C., after crystallization from water.

Elemental Analysis for C₈ H₁₀ N₂ O₂ : Calc'd: C, 57.82; H, 6.07; N, 16.86. Found: C, 58.60; H, 5.76; N, 16.65.

2-Amino-p-anisamide (4.99 g., 0.03 mole) is condensed with 3.68 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 3.84 g. of the title compound, m.p. 186°-188° C., after crystallization from ethanol.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ : Calc'd: C, 54.13; H, 5.34; N, 10.52. Found: C, 54.29; H, 5.50; N, 10.89.

EXAMPLE 34 5'-Chloro-2'-Sulfamyloxanilic acid ethyl ester. 70

2-Amino-4-chlorobenzenesulfonamide (4.13 g., 0.02 mole) is condensed with 2.46 ml. (0.022 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 3.04 g. of the title compound, m.p. 183°-187° C., after crystallization from ethanol.

Elemental Analysis for C₁₀ H₁₁ ClN₂ O₅ S: Calc'd: C, 39.2; H, 3.65; N, 9.14; S, 10.45. Found: C, 38.95; H, 3.65; N, 9.14; S, 10.86.

EXAMPLE 35 2'-Carboxy-4'-methoxyoxanilic acid 1-ethyl 2'-methyl ester. 58

6-Amino-m-anisic acid methyl ester (4.7 g., 0.0283 mole) is condensed with 3.48 ml. (0.311 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 5.27 g. of the title compound, m.p. 129°-133° C., after crystallization from ethanol.

Elemental Analysis for C₁₃ H₁₅ NO₆ : Calc'd: C, 55.51; H, 5.38; N, 4.98. Found: C, 55.72; H, 5.38; N, 5.37.

EXAMPLE 36 2',6'-Dichlorooxanilic acid ethyl ester. 100

The title compound is known in the literature: C.A.: 60 (1621a). It is crystallized from diethyl ether, m.p. 128°-130° C.

EXAMPLE 37 4'-Nitro-3'-(trifluoromethyl)oxanilic acid ethyl ester. 100/73

5-Amino-2-nitrobenzotrifluoride (6.18 g., 0.03 mole) is condensed with 3.7 ml. (0.033 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 6.07 g. of the title compound, m.p. 106°-110° C., after crystallization from ethanol.

Elemental Analysis for C₁₁ H₉ F₃ N₂ O₅ : Calc'd: C, 43.1; H, 2.96; N, 9.16. Found: C, 43.26; H, 2.95; N, 9.18.

EXAMPLE 38 4,4'-Oxydioxanilic acid diethyl ester. 34

The title compound is known in the literature: C.A.: 60 (P 3012b). It is crystallized from ethanol, m.p. 159°-162° C.

EXAMPLE 39 2'-Carbamyl-3'-methoxyoxanilic acid cyclohexyl ester. 91

6-Amino-o-anisamide is condensed with cyclohexyl oxalyl chloride to afford the title compound, m.p. 166°-169° C.

Elemental Analysis: C₁₆ H₂₀ N₂ O₅ : Calc'd: C, 59.99; H, 6.29; N, 8.75. Found: C, 60.17; H, 6.33; N, 8.69.

EXAMPLE 40 2'-Carbamyl-3'-methoxyoxanilic acid butyl ester. 98

6-Amino-o-anisamide is condensed with n-butyl oxalyl chloride to afford the title compound, m.p. 126°-129° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.17; N, 9.52. Found: C, 57.43; H, 6.46; N, 9.38.

EXAMPLE 41 2'-Carbamyl-3'-methoxyoxanilic acid sec-butyl ester. 100/70

6-Amino-o-anisamide is condensed with secondary butyl oxalyl chloride to afford the title compound, m.p. 119°-122° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₅ : Calc'd: C, 57.13; H, 6.17; N, 9.52. Found: C, 56.94; H, 6.44; N, 9.50.

EXAMPLE 42 2'-Carbamyl-3'-ethoxyoxanilic acid ethyl ester. 80

2-Amino-6-ethoxy-benzoic acid amide is condensed with ethyl oxalyl chloride to afford the title compound m.p. 142°-145° C.

EXAMPLE 43 2'-Carbamyl-3'-propoxyoxanilic acid ethyl ester. 52

2-Amino-6-propoxy-benzoic acid amide is condensed with ethyl oxalyl chloride to afford the title compound, m.p. 130°-133° C.

EXAMPLE 44 2'-Carbamyl-3'-isopropoxyoxanilic acid ethyl ester. 60

2-Amino-6-isopropoxy-benzoic acid amide is condensed with ethyloxalyl chloride to afford the title compound, m.p. 123°-125° C.

EXAMPLE 45 2'-Carbamyl-3'-n-butoxyoxanilic acid ethyl ester. 75

2-Amino-6-n-butoxy-benzoic acid amide is condensed with ethyl oxalyl chloride to afford the title compound, m.p. 120°-123° C.

EXAMPLE 46 (2-Naphthyl)oxamic acid ethyl ester. 76

The title compound is known in the literature: C.A. 43:697 g., m.p. 118°-120° C.

EXAMPLE 47 (1-Naphthyl)oxamic acid ethyl ester. 97

The title compound is known in the literature: C.A. 43:6973 g., m.p. 105°-107° C.

EXAMPLE 48 3', 4', 5'-Trimethoxyoxanilic acid ethyl ester. 63

The title compound is known in the literature: C.S. 68:9547 y, m.p. 132°-134° C.

Elemental Analysis for C₁₃ H₁₇ NO₆ : Calculated: C, 55.12; H, 6.05; N, 4.95. Found: C, 55.14; H, 6.26; N, 4.87.

EXAMPLE 49 3'-Methoxy-2'-N-Methylcarbamyloxanilic acid ethyl ester. 72

Slow addition of 4.98 g. (0.03 mole) of 6-amino-o-anisamide to a mixture of 57% NaH (1.32 g., 0.0315 mole) in 50 ml. dimethylformamide was carried out at room temperature. After the evolution of H₂ ceased, the mixture was cooled to 3° C. and 2.06 ml. (0.033 mole) of methyliodide was slowly added at 3°-5° C. The temperature was allowed to go up to room temperature and stir for 2 hours. The mixture was concentrated, the residue extracted into ethyl acetate-water, the mixture was basified, and the ethyl acetate layer was washed with water, brine and dried. Concentration gave a tan solid that was crystallized (ethanol), giving 0.45 g. (8%) of 6-amino-N-methyl-o-anisamide m.p. 186°-189° C.

Elemental Analysis for C₉ H₁₂ N₂ O₂ : Calculated: C, 59.98; H, 6.71; N, 15.55. Found: C, 60.42; H, 7.04; N, 15.42.

To a solution of 6-amino-N-methyl-o-anisamide (2.85 g., 0.0158 mole) and 2.54 ml. (0.0314 mole) of pyridine in 100 ml. of CH₂ Cl₂ at 10° C., is added 1.94 ml. (0.0174 mole) of ethyl oxalyl chloride over 5 minutes. After stirring for 2 hours at room temperature, diethyl ether is added and washed with water and cold dilute HCl. An insoluble solid is filtered off and crystallized from ethyl acetate-hexane, giving 0.3 g. of the title compound m.p. 119°-121° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₅ : Calculated: C, 55.71; H, 5.75; N, 10.00. Found: C, 55.91; H, 6.00; N, 9.94.

EXAMPLE 50 2'-Carbamyl-3'-(2-dimethylaminoethoxy)oxanilic acid ethyl ester, hydrochloride. 85

Ethyl oxalyl chloride (0.91 ml., 0.008 mole) is added to 1.81 g. (0.008 mole) of 2-amino-6-dimethylaminoethoxybenzamide at 10° C. in 100 ml. of CH₂ Cl₂ over a period of 5 minutes. After stirring overnight, the mixture is concentrated to dryness on a rotary evaporator and the residue is triturated with diethyl ether and filtered. The solid is crystallized from methanol, giving 1.89 g. of the title compound: m.p. 209°-211° C.

Elemental Analysis for C₁₅ H₂₂ ClN₃ O₅.O.15H₂ O: Calculated: C, 49.70; H, 6.2; N, 11.6; Cl, 9.78. Found: C, 49.92; H, 6.66; N, 11.64; Cl, 9.85.

The 2-amino-6-dimethylaminoethoxybenzamide reactant is prepared as follows:

To a solution of 14.06 g. (0.0728 mole) of 2,6-dinitrobenzonitrile in 270 ml. of tetrahydrofuran at 40° C., a solution prepared by adding 1.67 g. (0.726 mole) of sodium to 30 ml. of 2-dimethylaminoethanol is added over 20 minutes. The solution is refluxed for 3 hours, concentrated to dryness on a rotary evaporator and scrubbed three times with xylene. The residue is filtered with water, and crystallized from benzene-hexane, giving 7.79 g. of 2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile m.p. 89°-91° C.

Elemental Analysis for C₁₁ H₁₃ N₃ O₃ : Calculated: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.11; H, 5.70; N, 17.51.

To a solution of 7.17 g. (0.0305 mole) of 2-(2-dimethylaminoethoxy)-6-nitrobenzonitrile and 3.85 ml. of 85% hydrazine hydrate in 250 ml. of absolute ethyl alcohol at 40° C. is added small portions of Raney nickel. When the exotherm and evolution of gases ceases, the mixture is filtered and the filtrate concentrated to dryness. The residue is crystallized from ethyl acetate-hexane, giving 2.13 g. of 2-amino-6-dimethylaminoethoxybenzamide: m.p. 118°-121° C.

EXAMPLE 51 2-(Ethoxycarbonylcarboxamido)-4,5-dimethylbenzoic acid. 33.

To a solution of 4,5-dimethylanthranilic acid (3.30 g., 0.02 mole) and 3.22 ml. (0.04 mole) of pyridine in 50 ml. of tetrahydrofuran at 10° C., is added 2.46 ml. (0.022 mole) of ethyl oxalyl chloride over 5 minutes. After stirring for two hours at room temperature the solution is concentrated to dryness on a rotary evaporator. The residue is triturated with water and filtered, giving 4.27 g. of the title compound after crystallization (ethanol): m.p. 235°-239° C.

Elemental Analysis for: C₁₃ H₁₅ NO₅ : Calculated: C, 58.86; H, 5.70; N, 5.28. Found: C, 59.15; H, 5.73; N, 5.20.

EXAMPLE 52 (2-Carbamyl-4,5-dimethylphenyl)oxamic acid ethyl ester. 100

Liquid phosgene (55 g.) is added to a stirred solution of 30.1 g. (0.182 mole) of 4,5-dimethylanthranilic acid in 800 ml. of dioxane. The temperature is raised to 40°-45° C. and held for 2 hours, and then stirred overnight at room temperature. The mixture is filtered and the cake washed with diethyl ether, giving 33 g. of the isatoic anhydride: m.p.>300° C. The isatoic anhydride is then added to 435 ml. of N NH₄ OH, and the mixture stirred overnight at room temperature. The mixture is refluxed for 2 hours, cooled, filtered and crystallized(ethanol), giving 13.4 g. of 2-amino-4,5-dimethylbenzamide: m.p. 162°-7° C.

To a solution of 1.99 g. (0.0121 mole) of 2-amino-4,5-dimethylbenzamide and 1.95 ml. (0.0242 mole) of pyridine in 50 ml. of tetrahydrofuran at 10° C. is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5 minutes. The reaction is carried out and worked-up in a manner similar to example 51, giving 2.73 g. of the title compound after crystallization (ethanol), m.p. 190°-193° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₄ : Calculated: C, 59.08; H, 6.10; N, 10.60. Found: C, 58.82; H, 6.31; N, 10.41.

EXAMPLE 53 2'-Acetyl-3'-methoxyoxanilic acid ethyl ester. 46

To a solution of 2-amino-6-methoxyacetophenone (2.1 g., 0.0127 mole) and 2.05 ml. (0.0254 mole) of pyridine in 50 ml. of methylene chloride at 10° C., is added 1.49 ml. (0.0133 mole) of ethyl oxalyl chloride over 5 minutes. The reaction is carried out and worked-up in a manner similar to example 51, giving 2.06 g. of the title compound after chromatography on acidic silica gel: m.p. 70°-73° C.

Elemental Analysis for C₁₃ H₁₅ NO₅ : Calc'd: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.89; H, 5.66; N, 5.23.

EXAMPLE 54 2'-Carbamyl-3'-(2-hydroxypropoxy)oxanilic acid ethyl ester. 100

In a manner similar to example 50, but using, but using 1,2-propanediol instead of 2-dimethylaminoethanol, one isolates a 39% yield of 2-(2-hydroxy propoxy)-6-nitrobenzonitrile after crystallization (benzene): m.p. 121°-124° C.

Elemental Analysis for C₁₀ H₁₀ N₂ O₄ : Calculated: C, 54.05; H, 4.54; N, 12.61. Found: C, 54.24; H, 4.64; N, 12.67.

2-Amino-6-(2-hydroxypropoxy)benzamide is produced by reducing the benzonitrile in accordance with Example 50 in 78% yield after crystallization (ethyl acetate-hexane): m.p. 115°-118° C.

Elemental Analysis for C₁₀ H₁₄ N₂ O₃ : Calculated: C, 57.13; H, 6.71; N, 13.33. Found: C, 57.55; H, 6.56; N, 13.33.

To a solution of 2-amino-6-(2-hydroxy propoxy)benzamide (2.05 g., 0.00976 mole) and 1.57 ml. (0.01952 mole) of pyridine in 200 ml. of CH₂ Cl₂ at 10° C., is added 1.09 ml. (0.00976 mole) of ethyl oxalyl chloride over 20 minutes. The reaction is carried out and worked-up in a manner similar to example 51, giving 0.18 g. of the title material after chromatography on acidic silica gel and crystallization (ethyl acetate-hexane): m.p. 131°-135° C.

Elemental Analysis for C₁₄ H₁₈ N₂ O₆ : Calculated: C, 54.19; H, 5.85; H, 9.03. Found: C, 54.38; H, 6.09; N, 8.97.

EXAMPLE 55 (2-Carbamyl-3,5-dimethoxyphenyl)oxamic acid ethyl ester. 100/19 at 25 mg/kg

A solution of 1.96 g. (0.01 mole) of 4,6-dimethoxy anthranilamide in 50 ml. of methylene chloride is treated with pyridine and ethyl oxalyl chloride. After 1 hour the reaction mixture is filtered and the crude product is recrystallized from dimethylformamide-ethyl acetate to give 2.4 g. of product, m.p. 198°-208° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calculated: C, 52.70; H, 5.44; N, 9.46. Found: C, 52.75; H, 5.56; N, 9.54.

4,6-Dimethoxyanthranilamide is prepared as follows:

A mixture of 6.7 g. (0.03 mole) of 4,6-dimethoxy isatoic anhydride and 75 ml. of 1 M ammonium hydroxide is stirred 16 hours at room temperature. The solid is filtered off, dried and extracted with hot ethanol. The extracts are cooled and diethyl ether is added to give a first crop 1.2 g., mp. 197°-200° C. followed by a second crop of the desired amide, m.p. 117°-119° C., 2.3 g.

Elemental Analysis for C₉ H₁₂ N₂ O₃ : Calc'd: C, 55.09; H, 6.17; N, 14.28. Found: C, 55.01; H, 6.21; N, 14.12.

4,6-Dimethoxyisatoic anhydride is prepared from 4,6-dimethoxyanthranilic acid (H. Newman and R. Anzier, J. Org. Chem. 34, 3484 (1969)) and phosgene according to the method of E. C. Wagner and M. F. Fegley, Org. Synthesis 27, 45 (1947).

EXAMPLE 56 Oxalic acid (2-[2-aminocarbonyl-3-ethoxy carbonylcarbonylamino phenoxy]ethyl)ethyl ester. 82/26 at 10 mg/kg.

2-Amino-6-(2-hydroxyethoxy)benzamide is treated with two equivalents of pyridine and ethyl oxalyl chloride. The usual workup gives a white solid which is triturated with hot ethanol and filtered to give the product, m.p. 180°-182° C.

Elemental Analysis for C₁₇ H₂₀ N₂ O₉ : Calc'd: C, 51.51; H, 5.09; N, 7.07. Found: C, 51.39; H, 5.00; N, 7.11.

2-Amino-6-(2-hydroxyethoxy)benzamide is prepared by the following procedure:

A suspension of 6.0 g. of 2-(2-hydroxyethoxy)-6-nitrobenzonitrile on 30 ml. of ethanol and 4.3 ml. of hydrazine hydrate is added slowly to a suspension of 2.9 g. of Raney nickel in 50 ml. of ethanol at such a rate to keep the temperature at 65° C. The misture is heated at reflux for 1/2 hour after the addition is complete, filtered through Celite and evaporated to dryness. The solid is recrystallized from ethanol to give 5.3 g. (94%) of amide, m.p. 149°-151° C.

Elemental Analysis for C₉ H₁₂ N₂ O₃ : Calculated: C, 55.09; H, 6.17; N, 14.28. Found: C, 54.84; H, 6.17; N, 14.27.

The 2-(2-hydroxyethoxy)-6-nitrobenzonitrile is prepared as follows:

To a solution of 19.3 g. of 2,6-dinitrobenzonitrile in 500 ml. in tetrahydrofuran at reflux is added dropwise a solution of lithium hydroxyethoxide in tetrahydrofuran prepared by adding 62.5 ml. of 1.6 M butyllithium in hexane to a solution of 6.2 g. of ethylene glycol in 100 ml. of tetrahydrofuran at -78° C. and stirring for 1 hour. After all the ethoxide is added the reaction mixture is refluxed for 4 hours, cooled and evaporated to dryness. The resulting solid is extracted with hot benzene which yields 8.5 g. of product on cooling, m.p. 140°-142° C.

Elemental Analysis for C₉ H₈ N₂ O₄ : Calculated: C, 51.92; H, 3.87; N, 13.46. Found: C, 51.98; H, 3.92; H, 13.54.

EXAMPLE 57 [2-Carbamyl-3-(2-hydroxyethoxy)phenyl]oxamic acid ethyl ester 12 at 10 mg/kg per os; 49 at 30 mg/kg per os; 43 at 100 mg/kg per os.

To a suspension of 5.8 g. (30 mmole) of 2-amino-6-(2-hydroxyethoxy)benzamide in 100 ml. of dichloromethane is added 9.48 g. (120 mmole) of pyridine followed by 6.48 g. (60 mmole) of trimethylchlorosilane. After stirring 1 hour, 4.01 g. (30 mmole) of ethyl oxalyl chloride is added. The resulting solution is stirred for 48 hours, poured into dilute hydrochloric acid and the organic phase is separated. The aqueous layer is extracted with methylene chloride, the combined organic layers are washed with dilute hydrochloric acid and dried and evaporated. The residue is recrystallized from ethyl acetate-hexane to give 7.7 g. of product, m.p. 146°-148° C.

Elemental Analysis for C₁₃ H₁₆ N₂ O₆ : Calculated: C, 52.70; H, 5.44; N, 9.46. Found: C, 52.52; H, 5.42; N, 9.34.

EXAMPLE 58 (3-Benzyloxy-2-Carbamylphenyl)oxamic acid ethyl ester 55/22 at 25 mg/kg.

2-Amino-6-benzyloxybenzamide is treated with ethyl oxalyl chloride in the usual manner to give the ester, m.p. 151°-153° C.

Elemental Analysis for C₁₈ H₁₈ N₂ O₅ : Calculated: C, 63.15; H, 5.30; N, 8.18. Found: C, 63.31; H, 5.47; N, 8.36.

2-Amino-6-benzyloxybenzamide is prepared by the Raney nickel reduction of 2-benzyloxy-6-nitrobenzonitrile (E. Cortes and F. Walls, Boll Inst. Quim, Univ. Nach. Auton. Mex. 16, 71(1964); C.A. 63, 533c(1965) in the usual manner; m.p. 158°-160° C.

Elemental Analysis for C₁₄ H₁₄ N₂ O₂ : Calculated: C, 69.40; H, 5.83; N, 11.56. Found: C, 69.25; H, 6.10; N, 11.69.

EXAMPLE 59 N-Hydroxy-N'-phenyloxamide. 92.

The title compound is prepared by the method of Dimroth et al., Chem. Ber. 39, 3917; m.p. 165°-167° C.

Elemental Analysis for C₈ H₈ N₂ O₃ : Calculated: C, 53.33; H, 4.48; N, 15.55. Found: C, 53.30; H, 4.48; N, 15.07.

EXAMPLE 60 (4-Chlorophenyl)oxamic acid ethyl ester. 64

The title compound was prepared by the method disclosed in Farmaco, Ed. Sci. 22(9), 717-734 (1967); m.p. 149°-152° C.

Elemental analysis for C₁₀ H₁₀ NO₃ Cl: Calculated: C, 52.76; H, 4.43; N, 6.15. Found: C, 52.71; H, 4.40; N, 6.19.

EXAMPLE 61 (4-Dimethylaminophenyl)oxamic acid ethyl ester. 100/16 at 25 mg/kg per os.

The title compound was prepared by the method disclosed in Chem. Abstr., 72, P. 12413 M (1970); m.p. 166°-170° C.

Elemental Analysis for C₁₂ H₁₆ N₂ O₃.HCl: Calculated: C, 52.84; H, 6.28; N, 10.27; Cl, 13.00. Found: C, 52.93; H, 6.28; N, 10.27; Cl, 11.98.

EXAMPLE 62 [2-(Aminocarbonyl)-3-(dimethylamino)phenyl]oxamic acid ethyl ester. 54/21 at 25 mg/kg per os.

This is prepared from 2-amino-6-dimethylaminobenzamide and ethyl oxalyl chloride in the usual manner, m.p. 133°-135° C.

Elemental analysis for C₁₃ H₁₇ N₃ O₄ : Calculated: C, 55.90; H, 6.14; N, 15.05. Found: C, 56.04; H, 6.21; N, 14.54.

2-Amino-6-dimethylamino benzamide is prepared by the Raney nickel reduction of 2-dimethylamino-6-nitrobenzonitrile following the procedure presented in Example 50.

2-Dimethylamino-6-nitrobenzonitrile is prepared from molar equivalents of 2,6-dinitrobenzonitrile and dimethylamine hydrochloride in dimethylformamide in the presence of aqueous KOH.

EXAMPLE 63 [2-Carbamyl-3-(methylthio)phenyl]oxamic acid ethyl ester. 98/25 at 25 mg/kg per os.

This is prepared by ethyloxalation of 2-amino-6(methylthio) benzamide, m.p. 168°-170° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₄ S: Calculated: C, 51.05; H, 5.00; N, 9.92; S, 11.36. Found: C, 51.06; H, 4.92; N, 10.08; , 11.65.

2-Amino-6-(methylthio) benzamide is prepared by Raney nickel reduction of 2-(methylthio)-6-nitrobenzonitrile which is prepared from 2,6-dinitrobenzonitrile and methylmercaptan following the procedure set forth in Example 56.

EXAMPLE 64 (2-Aminocarbonyl-3-methylsulfinylphenyl)oxamic acid ethyl ester 44/23 at 25 mg/kg per os.

A mixture of 2.0 g. of [2-carbamyl-3-(methylthio)phenyl] oxamic acid ethyl ester and 1.44 g. of m-chloroperoxybenzoic acid in 200 ml. of methylene chloride is stirred for 2 hours. 0.6 g. of sodium bicarbonate in 20 ml. of water is added, the methylene chloride layer is separated, dried and evaporated. The residue is recrystallized from ethanol-diethyl ether, m.p. 164°-166° C.

Elemental Analysis for C₁₂ H₁₄ N₂ O₅ S:

Calc'd: C, 48.31; H, 4.73; N, 9.39; S, 10.74. Found: C, 48.15; H, 4.56; N, 9.26; S, 10.38. 

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R¹ is lower alkylamino or amino;R² is hydrogen, lower alkoxy, hydroxy (lower) alkoxy, halo or 2-(oxalyloxy)ethoxy; R³ is hydrogen, lower alkyl, lower alkoxy, halo or nitro; and R⁴ is hydrogen, lower alkyl or lower alkoxy;with the proviso that one of R², R³ and R⁴ must be other than hydrogen, or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 which is 2'-carbamyl-3'-methoxyoxanilic acid or a pharamceutically acceptable salt thereof.
 3. The compound of claim 1 which is 2'-carbamyl-3'-chlorooxanilic acid or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 which is 2'-carbamyl-4'-chlorooxanilic acid or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 which is 2'-carbamyl-4'-nitrooxanilic acid or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1 which is 2'-carbamyl-5'-methoxyoxanilic acid or a pharmaceutically acceptable salt thereof.
 7. The compound of claim 1 which is 2'-carbamyl-3'-ethoxyoxanilic acid or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 1 which is 2'-carbamyl-3'-propoxyoxanilic acid or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 1 which is 2'-carbamyl-3'-isopropoxyoxanilic acid or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 1 which is 2'-carbamyl-3'-n-butoxyoxanilic acid or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 1 which is 3'-methoxy-2'-N-methylcarbamyloxanilic acid or a pharmaceutically acceptable salt thereof.
 12. The compound of claim 1 which is (2-carbamyl-4,5-dimethylphenyl)oxamic acid or a pharmaceutically acceptable salt thereof.
 13. The compound of claim 1 which is 2'-carbamyl-3'-(2-hydroxypropoxy)oxanilic acid or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1 which is (2-carbamyl-3,5-dimethoxyphenyl)oxamic acid or a pharmaceutically acceptable salt thereof. 